Project summary Main goal of proposed research is to identify key regulators of metastasis in pancreatic ductal adenocarcinoma (PDA). I have developed a pancreatic organoid culture system and characterized organoid transplantation models to study PDA progression. To extend our knowledge on PDA metastasis, I have established the paired murine tumor and metastasis- derived organoids and profiled epigenetic landscape of these organoid series. Proposed research includes establishment and epigenetic profiling of mouse and human PDA organoids in collaboration with various experts in each field such as pancreatic cancer biology and cancer epigenetics. Having a clinical background as a veterinarian (D.V.M.), I have been trained in various preclinical models, particularly genetically engineered mouse models (GEMMs) and recently developed organoid culture models to study human disease. Under the K22 Career Development award, I will identify key transcription factors to regulate epigenetic alterations and dissect the role of axon guidance pathway in PDA metastasis using these preclinical models. To achieve my goal to become an independent investigator and a leader in PDA biology, I will acquire relevant knowledge and skills through collaborations and courses in cancer epigenetics, bioinformatics and translational medicine. In addition, taking advantage of available resources in Cold Spring Harbor Laboratory, I will be fully equipped with all necessary knowledge and skills. Successful completion of proposed research will reveal potential therapeutic targets and expand our current understanding of PDA progression.